The present invention relates to methods of using desloratadine to inhibit generation of pro-inflammatory cytokines, e.g., IL-4 and IL-13.
Mast cells and basophils play a role in allergic and inflammatory diseases. These cells produce a wide variety of mediators such as prostaglandins, e.g., prostaglandin D2, leukotrienes, e.g., leukotriene C4 cytokines and histamine. Cytokines are polypeptides secreted by cells that affect the function of other cells. Cytokines, including interleukins, differ widely in the types of cells affected and in biological activities exhibited. Desloratadine, a non-sedating antihistamine, is disclosed by Lippert, U., et al, Experimental Dermatology, 1995, Vol. 4, 272-276 to be active in vitro in inhibiting the release of the cytokines IL-6 by up to 40% and IL-8 by up to 50% from human mast and basophilic cell lines. Human Fcxcex5 RI+ cells play a considerable pro-inflammatory role through the release of histamine, tryptase and chymase. However, since human mast and basophilic cell lines are defective in signaling through the high affinity immunoglogulin-E(IgE) receptor, Fcxcex5 RI, it is difficult to predict what effect, if any, desloratadine has on the IgE-mediated release of IL-6 and IL-8. . S. Molet, et al., Clinical and Experimental Allergy, 1997, Vol. 27, pages 1167-1174 disclose that desloratadine reduces histamine-induced release of IL-6 and IL-8 in an in vitro study in endothelial cells. Kleine-Tebbe, J., et al, J. Allergy Clin. Immunol. 1994, Vol. 93, No. 2, pages 494-500 disclose that desloratadine inhibits IgE- and non-IgE-mediated histamine release in an in vitro study in human basophilic leukocyte cells.
Human basophils are a major source of the cytokines, IL-4 and IL-13 that are produced in vitro in mixed leukocyte cultures. Production of IL-4 and IL-13 by basophils may play a role in modulating a variety of activities that are involved in the pathogenesis of allergic inflammatory conditions. For example, IL-4 and IL-13 each induce secretion of IgE- and IgG-4 by human B-cells. (See Schroeder, J. T.,xe2x80x9cThe role of basophil-cytokine networks in asthma.xe2x80x9d In Asthma and Allergic Diseases: Physiology, Immunopharmacology, and Treatment, Editors: G. Marone, K. F. Austen, S T Holgate, A. B. Kay, L. M. Lichtenstein, Academic Press, San Diego, 75-84, 1998a). However, there is a no information on the effect of desloratadine on the generation of cytokines such as IL-4 and IL-13 in basophils or any other cell types. One study by Gibbs, et al. Naunyn Schmiedebegs Arch. Pharmacol, 1998, Vol. 357: 573-578 reports moderate (50%) inhibition of IL-4 and IL-13 secretion in vitro in basophilic cells using relatively high concentrations of terfenadine, a non-sedating antihistamine. This study did not test whether the terfenadine concentrations used were toxic. The FDA has withdrawn the two terfenadine NDAs because of the finding that terfenadine was no longer safe for cardiac reasons for use in treating seasonal allergic rhinitis.(Federal Register, Oct. 5,1998, Vol. 63, page 53444).
There is a need for a safe, effective therapy to inhibit secretion of pro-inflammatory cytokines such as IL-4 and IL-13 to treat disease states, for example, allergic and/or inflammatory conditions.
The present invention provides a method of inhibiting generation of IL-4 and IL-13 in a human patient in need of such inhibiting which comprises administering to such a patient an effective amount of desloratadine.
Typically. IL-4 and IL-13 is generated from human basophils as well as other cells, e.g., human B-cells.
The present invention also provides a method of inhibiting generation of IL-4 and IL-13 from human basophils in a patient exhibiting the symptoms of an allergic and/or inflammatory condition which comprises administering to such a patient an amount of desloratadine effective to inhibit the generation of IL-4 and IL-13 and to concurrently treat the symptoms of such an allergic and/or inflammatory conditions.
The present invention also provides a method of blocking generation of pro-inflammatory cytokines in a patient in need of such blocking which comprises administering to such a patient an effective amount of desloratadine.
The present invention also provides a method of inhibiting secretion of pro-inflammatory cytokines from human basophils in a patient in need of such inhibiting which comprises administering to such a patient an effective amount of desloratadine.
The preferred pro-inflammatory cytokines are IL-4 and IL-13.
The patients in need of such inhibiting are those having symptoms of allergic/inflammatory conditions of the airway passages, skin, eyes and intestinal tract.
The present invention also provides a method of treating a patient exhibiting the symptoms of allergic/inflammatory conditions of the skin, eyes, intestinal tract,and/or upper and lower airway passages which comprises administering to such a patient an effective amount of desloratadine.
The patients in need of such inhibiting are those having symptoms of an allergic and/or inflammatory condition of the skin, eyes, intestinal tract, and/or the upper and lower airway passages.
The present invention also provides a method of treating a disease state that has an allergic component and an inflammatory component which comprises administering to a patient in need of such treatment an amount of desloratadine effective to produce an anti-inflammatory effect.
The present invention also provides a method of treating and/or preventing allergic asthma and inhibiting secretion of IL-4 and IL-13 in a patient in need of such treating which comprises administering to such a patient an effective amount of desloratadine.
The present invention also provides a method of treating and/or preventing allergic rhinitis and inhibiting secretion of IL-4 and IL-13 in a patient in need of such treating which comprises administering to such a patient an effective amount of desloratadine.
The present invention also provides a method of treating and/or preventing atopic dermatitis and inhibiting secretion of IL-4 and IL-13 in a patient in need of such treating which comprises administering to such a patient an effective amount of desloratadine.
The present invention also provides a method of treating and/or preventing urticaria and inhibiting secretion of IL-4 and IL-13 in a patient in need of such treating which comprises administering to such a patient an effective amount of desloratadine.
The present invention also provides a method of treating IL-4 and IL-13 mediated disease states in a patient in need of such treating which comprises administering to such patients an effective amount of desloratadine to inhibit generation of IL-4 and IL-13.
The effective amount of desloratadine is an amount sufficient to inhibit and preferably block generation of IL-4 and IL-13 from human cells.
The present invention also provides a method of inhibiting generation of IL-4 and IL-13 from human basophils in a patient exhibiting the symptoms of an allergic and/or inflammatory condition of the skin, eyes, intestinal tract, and/or the upper and lower airway passages which comprises administering to such a patient an amount of desloratadine effective to inhibit the generation of IL-4 and IL-13 and to concurrently treat the symptoms of such an allergic and/or inflammatory condition.